Inactivation of Endothelial Small/Intermediate Conductance of Calcium-Activated Potassium Channels Contributes to Coronary Arteriolar Dysfunction in Diabetic Patients

Background-—Diabetes is associated with coronary arteriolar endothelial dysfunction. We investigated the role of the small/ intermediate (SK_Ca /IK_Ca) conductance of calcium-activated potassium channels in diabetes-related endothelial dysfunction. Methods and Results-—Coronary arterioles (80 to 150 lm in diameter) were dissected from discarded right atrial tissues of diabetic (glycosylated hemoglobin = 9.6±0.25) and nondiabetic patients (glycosylated hemoglobin 5.4±0.12) during coronary artery bypass graft surgery (n=8/group). In-vitro relaxation response of precontracted arterioles was examined in the presence of the selective SK_Ca/IK_Ca activator NS309 and other vasodilatory agents. The channel density and membrane potential of diabetic and nondiabetic endothelial cells was measured by using the whole cell patch-clamp technique. The protein expression and distribution of the SK_Ca /IK_Ca in the human myocardium and coronary arterioles was examined by Western blotting and immunohistochemistry. Our results indicate that diabetes significantly reduced the coronary arteriolar response to the SK_Ca /IK_Ca activator NS309 compared to the respective responses of nondiabetic vessels (P<0.05 versus nondiabetes). The relaxation response of diabetic arterioles to NS309 was prevented by denudation of endothelium (P=0.001 versus endothelium-intact). Diabetes significantly decreased endothelial SK_Ca /IK_Ca currents and hyperpolarization induced by the SK_Ca /IK_Ca activator NS309 as compared with that of nondiabetics. There were no significant differences in the expression and distribution of SK_Ca /IK_Ca proteins in the coronary microvessels. Conclusions-—Diabetes is associated with inactivation of endothelial SK_Ca /IK_Ca channels, which may contribute to endothelial dysfunction in diabetic patients.